Stereospecific total synthesis of ajugarin-IV

Tetrahedron Letters,Vol.23,No.l7,pp Printed in Creat Britain

STEREOSPECIFIC

TOTAL

Andrew Department

1751-1754,1982

S.

SYNTHESIS

Kende

and

0040-4039/82/171751-04$03.00/O 01982 Pergamon Press Ltd.

OF AJUCARIN-IV

Bruce

Roth

of Chemistry, Untversity of Rochester Rochester, New York 14627 lsao Kubo

Diviston

Summary

of Entomology and Parasitology, Colleqe of Natural Resources University of Californta, Berkeley, Caltfornla 94720

A stereospecific

lnsecttcrde

sequence Formation

ajuqarin-IV.

-21 by successive

use of the

from the octalindlone of the

reaqents

butenohde

2 leads

portion

In 21 steps

is conveniently

trts(tr~methylsiloxy)ethylene

and

to the new achteved

from acid

ketenyhdenetrtphenyl-

phosphorane.

Current

efforts

the antifeedant clerodane plant

remota

epoxlde

the total

Insecticidal

antifeedants

Ajuqa

C-4

toward

and

recently

We now describe

a stereospecific

synthesis

natural

of any

regio-

and

stereoselective

more

hiqhly

oxygenated

Our

starting

the dithioketal

methylene verted

to Its Me3SI

minatlon NMR

6 7.12

(d,

that

was the octalindione was converted

enol ether

IS

serve

been

stimulated

class.

Among

unique

uttllzes

that

both the 3

ajuqarlns.

comprises

an lnterestlnq

as prototypes

for

by the

medicinal

In lacklnq

described

by a route

sequence

could

J=lOHr,

reflux,

lH),

6.93

(d,

the first

series

synthesis

was now set for the two-step

enone

MeLt gave

transposition a single 1751

transformed 90°,

of

of the

(NBS,

the conjugated (s,

1H).

developed tertiary

I) to by

2 was con-

O”I and dehydrobro-

(s,

by Dauben

alcohol

followed

ketone

ketone

4.60

(Scheme

70% of the AB trans

numberlnq),

brominatlon

4.63

12 hrs)

of 4 qave

(ajugarin

gave

lH1,

DMSO,

allylatlon

C-7

This

J=lOHz,

the

5 with

C-6

by selective 3 hrs).

was selectively

(4 eqt,

Reductive

staqe

of ketone

z4 which

To functionallze

followed

DMF,

5.

Thus

reaction

(l_12

of the previously

by Ph3P=CH2

to the enone

5, mp 47-49°.6

(LIBr-L12C03,

This

have of this

of the East African

of ajuqarin-IV

tnsecttcrde.

transformations

hydrolyses

ketone

leaves

aJugarlrrlV

characteristic

synthesis

members

ajuqarlns.

This

3.5

total

ajuqarin

material

HgC12-Cd Co3

component

substituent

dlterpenes’

for certain

from the bitter

the trace

oxygen

of clerodane

noted

Isolated

(Lablatae)

and C-16

synthesis

properties

6 [ IR 1H).

1670 C-II-‘,

90%1.

The

and Michno.’

tn nearly

quantitative

yield.

1752

Scheme

I

2 X=Y=O 2 X=S(CH2) 4 X=0,

Scheme

3S, Y=O

Y=CH2

II

y$$y& lJ

R’=R*=O

12 R’=H,

z R*=OH

13 R’=OH,

R*=H

14 R’=H,

Is

R*=OMOM

_.jLj?

R’=H,

R2=CH20H,

16 R’=H,

R*=CHO,

lJ R1=R3=C02CH3, 18 R’=H,

CH302k

’ &tl

19 R’=MOM, g

R’=H,

U

R’=COCH3,

R*=H

R*=H R*=H

R*=H

R2=R3=C02CH3

;!j!Lj?P”

CH,O&

R3=CH20H R3=C02H

&OCH, -22

1753

Unfortunately, drnium

treatment

chlorochromate

of the

desired

enone

be suppressed

25O, 2 hrs)

5.00

lH),

metal

the

ll_,

rn which

”

shown.

the

Reaction

the equatorial

stereochemistry ketone

with

Rf for 12 = 0.15,

6 3.89

1lHz.

J=4.5,

lH),

fi

with

tempt

problems

to direct

the bulky

(6 eqt Jones ing dlester having

E

dicating

C-4

for

C-4

CH20H kinetic

transformed

(1.5

qave

25”,

stlrrlng

12 h). with

IV was accomplished 2 hrs)

followed

dlester

diester

the

saponification

90% of the monoester

brief

t-BuOH,

lo,

aq HCO3

H202

By this

18.

side chain. ester

(3 eqt Ac20, gave

of all volatiles

core now assured, An interesting KOH,

hydrolyzed Et3N,

DMAP,

to the CH2C12,

in 95% yield.

of 21 with

at reduced

solution

excess

pressure

Sla2BH

dlol asslqned

hydroxy

then

reaction -14 was

remaining

24 hrs) ester

10 hr)

Conversion (5 eqt,

and addition

in the

acid Is,

was developed reflux,

CICOCOCI

possl-

the

equlllbratlnq

5 eqt

the dlolefin

25”,

in-

to the desired

the principal

CH30H,

1H)

the desired

pH 5, 24 hrs) and sequence

eqt

asslqned

under

yield.

in

dlester

2Hz.

we explored

with

In 53% overall

(1.1

The

to the aldehyde

2S”,

gave

the correspond-

J=4.5,

was a single

at-

by use of

H202)

to qlve

reactlon

stereo-

to the diaclds

completely

stereospecific

s

alk.

(dd,

to react

oxldatlon

and

respectively.

qroup

25O, 12 hrs)

the acetate2l_

Reaction

CH2N2

convert-

An initial

substituent

In hand,

was allowed

DMF,

was quantitatively

In two steps.

by removal

from

2

reqio-

II).

was therefore

vlnyl

2-methyl-2-butene,

unhindered

Acetylatlon dilute

when

in the ahcycllc

which

(g)

(NMR

2 da).

the

then

6 2.71

out the dlslamylborane

stereolsomer

butenollde

of the

C-4

2S”,

of

(SI qel,

mp 51-52O

was oxldlzed

assignments

of the exocyclrc

(7 eqt PDC,

stereochemistry

Isomer

at

a 20 1 mixture

be quantitatively

2 hrs,

LI.

ketone,

separated

(Scheme

with

(10 eqt

confiquratlon

2,

CH20H

0“+25’,

slqnal

With these

sole product

eqt,

the slnqle

blem was to construct

aq THF,

the

sites

When how-

saturated

gave

we examined

dlol mixture

‘H-nmr

Rf = 0.28

by carrylnq 12 Indeed,

was oxidized

to the desired

With correct

selective

series

CH2C12,

3.1 hexane-EtOAc)

(SI gel,

The

proton.

at reflux

oxidation

2 CH2N2

0.28

stereochemistry.

conditions.

This

Is.

NaClO

and

12 could

30%) and esterlfled

at 400 MHz a clean

the hydroboratlon

5 hours

structure

with

Rf = 0.37

COOCH3

equatorial than

12 hrs,

Alcohol

THF,

source

20 mln)

the equatorial

This

at C-4.

proton

IPr2NEt,

established,

to yield

mixture

83% of pure

at the olefinic

(4 eqt Sia2BH, epimeric

O”+2So,

exhibited

an equatorial

of driving

rather --THF

and 3,

C-4

of 14 at C-4

of dlols

Me2C0,

Rf = 0.37

equatorial bility

rgt,

3 eqt

thus

inseparable

was reduced.

was readily

to qive

3H)l.

(2 eqt,

functlonallzatlon

dlslamylborane

a 1 1 mixture

J=7Hz,

of the B-ring

hydroboratlon

reaqent

80% yield

(d,

a nearly

equatorial

-42O.

mixture

Rf for 13 = 0.40)

0.87

of selective

Et20,

s,

of

to a single

the expected

This

5.

lH),

(br

55% yield. conversion

of added

transformed

(4 eqt,

epimer

6 5.92

for direct

the ally1 qroup

absence

IS asslqned

CICH20CH3

With the stereochemistry chemical

In which

LiAIH4

12 and the axial

ed to the MOM ether

THF,

lo,

1 was quantltatlvely

3 1 hexane-EtOAc, (dd,

NH3,

authors,

py,

NMR

condltlons 10 afforded EtOH)

with 40% 8 could

(6 eqt Cr03*2

in approximately

standard

wrth pyn-

8 toqether

by other

condrtions

1660 cm -‘,

(IR

out in the complete

enone

of this

alcohol

LI,

the latter

was obtained

1 using

byproduct

was carried

E-methyl

3H)]

condltlons

compound

not mentioned

Under

mp 59-61”

s,

of enone (e.g.,

Dauben-Michno

exo-methylene

srde reaction,

z,

(br

2 and the

90 mln),

-33’,

standard

reagent.’

enone

1.97

alcohols

alcohol

reduction

THF,

NH3,

1H).

reduction

to saturated

of the desired ever

(s,

under

unexpected

crystalllne

4.75

Drssolvinq enones

This

1.

alcohol

ZO-30% of the undesired

by use of the Collins

CH2C12, (s,

of this

gave

g

through to give (6N

followed

of c

pro-

HCI. by

to a]ugarln

CH2C12,

25O,

of 15 eqt of neat

tris-

1754

(trtmethylslloxylethylene, of the crystalhne (m.

Reaction

1Hll.

superior

(+)-ajugarin-lV

Into

(1).

to those

12 hrs of heatinq

ketone

of this

to alternative

Identical e

l3 then

hydroxy

22,

hydroxy

reagents

ketone

for our

mp 175-176°.16

of the

(+I-ajugarln-I

natural

at 90’ followed

[ NMR .

mp 128 131 o

series)

Our

product.

by appropriate

with

6 4.27 (s,

ketenylldene

l5 for

by actd hydrolyses 2H1,

(m,

lH1,

triphenylphosphorane

1 hr at 25’ qave

racemtc

aluqarin

Studies

are in proqress

functionalizatlon

2.30

IV had

IR,

UV,

of the C-18

angular

56%

2.15

l4 (vastly

In 86% yteld

crystalline

‘H-NMR

to convert

qave

and MS

our

IntermedIate 17 group.

methyl

References 1.

The first total synthesis of trans-clerodane, (?I-annonene, was achieved by Takahashl, S., Kusumi, T., Kaklsawa, H. ChamistrY Lett. m 515. Other recent approaches include (al Luteijn, J. M., deGrcot, A. Tetrahedron Lett. m 789, Ibid. 1980, 4129 (b) ColdsmIth D. J., SrouJi, C., Kwonq, C. J. Orq. Chem.m, 5, 3182. Seelszference 8.

2.

Kubo,

I.,

3.

Kubo. U.-W.,

I., Kldo. M., Balogh-Nalr,

4.

Kltahara,

5.

WIlllams, J. R., Sarkislan, G. M. Synthesis 1974, 32. R. A. J., Hannah, D. J. Synth. Comm. 1979, 2, 301.

6.

Ardon-Jlmlnez,

7.

Dauben,

a.

For a related allylic enone transposition In an approach deCroot, A. J. Orq. Chem. 1981. 46, 3448.

9.

Collins,

10.

DJerassl,

11.

Stork, G., Darling, D. W., Walshaw, K.

12.

Krublner,

13.

Wissner,

14.

Nlcklsch,

15.

(a) Donovan, Frltsch, W.,

16.

All Intermediates In our synthetic had mp 119-120.5°C. and 400 MHz lH-NMR spectra In agreement with the Synthetic (+I-ajuqarin-IV had mp 175-6’C. UV (CH30H) vmax 212nm. assigned structures. 400 MHz 1H-NMR (CDCl3) 6 5.84 (br s, e 16,000. IR (CH Cl21 1785, 1750, 1730, 1635 cm-l. llHz, 1H). 1.97 (s, 3H). 1.21 (s, 3H). 0.82 (d, 1H). 4.74 (br s, 2?-l 1, 4.60 (dd, J=4.5, J=7Hz, 3H), 0 78 (s, 3H). Synthetic aluqarln-IV exhibited lnsectlcldal actlvltv aaalnst the silkworm. Bombyx marl. at 1500 ppm (LD951, but only qrowth inhibitory actlvlty against the pink bollworm. Pectlnophora qossyplella at 1500 ppm (ED50) with artlflclal diet feedlnq bloassay. This activity IS about one third of natural ajugarln-IV. Natural

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Y.,Yoshikoshl,

A.,

W. G.,

J. C., C.,

A. A. K.,

A.,

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Hess, Gals,

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E.

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I.,

Lee,

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Trans,

example,

I 1978,

Chem.

to alugarln-I

Lett.

see Smith,

1461.

Sot.

86,

P. J. Orq.

see LutelJn,

1968, 1959.

J. M.,

3363. 81,

1761,

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1715.

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1980,

113,

J. E. Tetrahedron Avery, M. A., McMurry, V., Ruschiq, H. Ann. 1966, 669, 195. -= [aD]

897.

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Perkln

D. J. Am. Chem. Sot. 196y, J. Chem. Sot. 1964, 1029.

Chem. W.,

T.

Mitscher,

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aJugarln-IV

S. B.

Olda,

D. M. J. Orq.

W. W.,

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2038. Lett.

1979,

3287.

(b)

= -57.5’.

sequencehad IR, MS or mlcroanalysls

17.

Partial supoort of thts work by grant USPHS, IS gratefully acknowledqed.

(Received in USA 26 January

CA-18846,

1982)

awarded

by the

National

Cancer

lnstttute,